Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 303 (5657): 523-527

Copyright © 2004 by the American Association for the Advancement of Science

Editing of CD1d-Bound Lipid Antigens by Endosomal Lipid Transfer Proteins

Dapeng Zhou,1* Carlos Cantu, III,2* Yuval Sagiv,1 Nicolas Schrantz,2 Ashok B. Kulkarni,3 Xiaoyang Qi,4 Don J. Mahuran,5 Carlos R. Morales,6 Gregory A. Grabowski,4 Kamel Benlagha,1 Paul Savage,7 Albert Bendelac,1{dagger} Luc Teyton2{dagger}

Abstract: It is now established that CD1 molecules present lipid antigens to T cells, although it is not clear how the exchange of lipids between membrane compartments and the CD1 binding groove is assisted. We report that mice deficient in prosaposin, the precursor to a family of endosomal lipid transfer proteins (LTP), exhibit specific defects in CD1d-mediated antigen presentation and lack V{alpha}14 NKT cells. In vitro, saposins extracted monomeric lipids from membranes and from CD1, thereby promoting the loading as well as the editing of lipids on CD1. Transient complexes between CD1, lipid, and LTP suggested a "tug-of-war" model in which lipid exchange between CD1 and LTP is on the basis of their respective affinities for lipids. LTPs constitute a previously unknown link between lipid metabolism and immunity and are likely to exert a profound influence on the repertoire of self, tumor, and microbial lipid antigens.

1 Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
2 Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA.
3 National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
4 Children Hospital Medical Center, Cincinnati, OH 45229–3039, USA.
5 Department of Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1X8, Canada.
6 Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 2B2, Canada.
7 Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602–5700, USA.

Back to Top

* These authors contributed equally to this work.

{dagger} These authors contributed equally to this work. To whom correspondence should be addressed. E-mail: abendela{at}bsd.uchicago.edu (A.B.); lteyton{at}scripps.edu (L.T.)

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Role for lysosomal phospholipase A2 in iNKT cell-mediated CD1d recognition.
C. Paduraru, J. S. Bezbradica, A. Kunte, R. Kelly, J. A. Shayman, N. Veerapen, L. R. Cox, G. S. Besra, and P. Cresswell (2013)
PNAS 110, 5097-5102
   Abstract »    Full Text »    PDF »
Globosides but Not Isoglobosides Can Impact the Development of Invariant NKT Cells and Their Interaction with Dendritic Cells.
S. Porubsky, A. O. Speak, M. Salio, R. Jennemann, M. Bonrouhi, R. Zafarulla, Y. Singh, J. Dyson, B. Luckow, A. Lehuen, et al. (2012)
J. Immunol. 189, 3007-3017
   Abstract »    Full Text »    PDF »
Deciphering the Role of CD1e Protein in Mycobacterial Phosphatidyl-myo-inositol Mannosides (PIM) Processing for Presentation by CD1b to T Lymphocytes.
D. Cala-De Paepe, E. Layre, G. Giacometti, L. F. Garcia-Alles, L. Mori, D. Hanau, G. de Libero, H. de la Salle, G. Puzo, and M. Gilleron (2012)
J. Biol. Chem. 287, 31494-31502
   Abstract »    Full Text »    PDF »
Regulation of the Actin Cytoskeleton by Rho Kinase Controls Antigen Presentation by CD1d.
R. M. Gallo, M. A. Khan, J. Shi, R. Kapur, L. Wei, J. C. Bailey, J. Liu, and R. R. Brutkiewicz (2012)
J. Immunol. 189, 1689-1698
   Abstract »    Full Text »    PDF »
Distinct APCs Explain the Cytokine Bias of {alpha}-Galactosylceramide Variants In Vivo.
L. Bai, M. G. Constantinides, S. Y. Thomas, R. Reboulet, F. Meng, F. Koentgen, L. Teyton, P. B. Savage, and A. Bendelac (2012)
J. Immunol. 188, 3053-3061
   Abstract »    Full Text »    PDF »
Saposins utilize two strategies for lipid transfer and CD1 antigen presentation.
L. Leon, R. V. V. Tatituri, R. Grenha, Y. Sun, D. C. Barral, A. J. Minnaard, V. Bhowruth, N. Veerapen, G. S. Besra, A. Kasmar, et al. (2012)
PNAS 109, 4357-4364
   Abstract »    Full Text »    PDF »
Mutation of a Positively Charged Cytoplasmic Motif within CD1d Results in Multiple Defects in Antigen Presentation to NKT Cells.
J. H. Shin, J.-Y. Park, Y. H. Shin, H. Lee, Y.-K. Park, S. Jung, and S.-H. Park (2012)
J. Immunol. 188, 2235-2243
   Abstract »    Full Text »    PDF »
Structure of saposin A lipoprotein discs.
K. Popovic, J. Holyoake, R. Pomes, and G. G. Prive (2012)
PNAS 109, 2908-2912
   Abstract »    Full Text »    PDF »
Dendritic Cell Internalization of {alpha}-Galactosylceramide from CD8 T Cells Induces Potent Antitumor CD8 T-cell Responses.
D. H. Choi, K. S. Kim, S. H. Yang, D. H. Chung, B. Song, J. Sprent, J. H. Cho, and Y. C. Sung (2011)
Cancer Res. 71, 7442-7451
   Abstract »    Full Text »    PDF »
Identification of Self-lipids Presented by CD1c and CD1d Proteins.
N. A. Haig, Z. Guan, D. Li, A. McMichael, C. R. H. Raetz, and X.-N. Xu (2011)
J. Biol. Chem. 286, 37692-37701
   Abstract »    Full Text »    PDF »
Fine tuning by human CD1e of lipid-specific immune responses.
F. Facciotti, M. Cavallari, C. Angenieux, L. F. Garcia-Alles, F. Signorino-Gelo, L. Angman, M. Gilleron, J. Prandi, G. Puzo, L. Panza, et al. (2011)
PNAS 108, 14228-14233
   Abstract »    Full Text »    PDF »
Crystal structure of human CD1e reveals a groove suited for lipid-exchange processes.
L. F. Garcia-Alles, G. Giacometti, C. Versluis, L. Maveyraud, D. de Paepe, J. Guiard, S. Tranier, M. Gilleron, J. Prandi, D. Hanau, et al. (2011)
PNAS 108, 13230-13235
   Abstract »    Full Text »    PDF »
Peroxisome Proliferator-Activated Receptor {gamma}-Regulated Cathepsin D Is Required for Lipid Antigen Presentation by Dendritic Cells.
B. Nakken, T. Varga, I. Szatmari, L. Szeles, A. Gyongyosi, P. A. Illarionov, B. Dezso, P. Gogolak, E. Rajnavolgyi, and L. Nagy (2011)
J. Immunol. 187, 240-247
   Abstract »    Full Text »    PDF »
Diverse Endogenous Antigens for Mouse NKT Cells: Self-Antigens That Are Not Glycosphingolipids.
B. Pei, A. O. Speak, D. Shepherd, T. Butters, V. Cerundolo, F. M. Platt, and M. Kronenberg (2011)
J. Immunol. 186, 1348-1360
   Abstract »    Full Text »    PDF »
Calreticulin Controls the Rate of Assembly of CD1d Molecules in the Endoplasmic Reticulum.
Y. Zhu, W. Zhang, N. Veerapen, G. Besra, and P. Cresswell (2010)
J. Biol. Chem. 285, 38283-38292
   Abstract »    Full Text »    PDF »
A Threonine-Based Targeting Signal in the Human CD1d Cytoplasmic Tail Controls Its Functional Expression.
J. Liu, D. Shaji, S. Cho, W. Du, J. Gervay-Hague, and R. R. Brutkiewicz (2010)
J. Immunol. 184, 4973-4981
   Abstract »    Full Text »    PDF »
An Alternative Path for Antigen Presentation: Group 1 CD1 Proteins.
J. L. Strominger (2010)
J. Immunol. 184, 3303-3305
   Full Text »    PDF »
Activation state and intracellular trafficking contribute to the repertoire of endogenous glycosphingolipids presented by CD1d.
K. Muindi, M. Cernadas, G. F. M. Watts, L. Royle, D. C. A. Neville, R. A. Dwek, G. S. Besra, P. M. Rudd, T. D. Butters, and M. B. Brenner (2010)
PNAS 107, 3052-3057
   Abstract »    Full Text »    PDF »
Commensal Microbiota and CD8+ T Cells Shape the Formation of Invariant NKT Cells.
B. Wei, G. Wingender, D. Fujiwara, D. Y. Chen, M. McPherson, S. Brewer, J. Borneman, M. Kronenberg, and J. Braun (2010)
J. Immunol. 184, 1218-1226
   Abstract »    Full Text »    PDF »
A Central Role for Transcription Factor C/EBP-{beta} in Regulating CD1d Gene Expression in Human Keratinocytes.
H. Sikder, Y. Zhao, A. Balato, A. Chapoval, R. Fishelevich, P. Gade, I. S. Singh, D. V. Kalvakolanu, P. F. Johnson, and A. A. Gaspari (2009)
J. Immunol. 183, 1657-1666
   Abstract »    Full Text »    PDF »
Lysosomal recycling terminates CD1d-mediated presentation of short and polyunsaturated variants of the NKT cell lipid antigen {alpha}GalCer.
L. Bai, Y. Sagiv, Y. Liu, S. Freigang, K. O. A. Yu, L. Teyton, S. A. Porcelli, P. B. Savage, and A. Bendelac (2009)
PNAS 106, 10254-10259
   Abstract »    Full Text »    PDF »
CD1c bypasses lysosomes to present a lipopeptide antigen with 12 amino acids.
I. Van Rhijn, D. C. Young, A. De Jong, J. Vazquez, T.-Y. Cheng, R. Talekar, D. C. Barral, L. Leon, M. B. Brenner, J. T. Katz, et al. (2009)
J. Exp. Med. 206, 1409-1422
   Abstract »    Full Text »    PDF »
Natural Lipid Ligands Associated with Human CD1d Targeted to Different Subcellular Compartments.
W. Yuan, S.-J. Kang, J. E. Evans, and P. Cresswell (2009)
J. Immunol. 182, 4784-4791
   Abstract »    Full Text »    PDF »
Regulation of multiple myeloma survival and progression by CD1d.
E. Spanoudakis, M. Hu, K. Naresh, E. Terpos, V. Melo, A. Reid, I. Kotsianidis, S. Abdalla, A. Rahemtulla, and A. Karadimitris (2009)
Blood 113, 2498-2507
   Abstract »    Full Text »    PDF »
Ig-Like Transcript 4 Inhibits Lipid Antigen Presentation through Direct CD1d Interaction.
D. Li, L. Wang, L. Yu, E. C. Freundt, B. Jin, G. R. Screaton, and X.-N. Xu (2009)
J. Immunol. 182, 1033-1040
   Abstract »    Full Text »    PDF »
Enhanced Early Expansion and Maturation of Semi-Invariant NK T Cells Inhibited Autoimmune Pathogenesis in Congenic Nonobese Diabetic Mice.
A. Ueno, J. Wang, L. Cheng, J. S. Im, Y. Shi, S. A. Porcelli, and Y. Yang (2008)
J. Immunol. 181, 6789-6796
   Abstract »    Full Text »    PDF »
Congenic Analysis of the NKT Cell Control Gene Nkt2 Implicates the Peroxisomal Protein Pxmp4.
J. M. Fletcher, M. A. Jordan, S. L. Snelgrove, R. M. Slattery, F. D. Dufour, K. Kyparissoudis, G. S. Besra, D. I. Godfrey, and A. G. Baxter (2008)
J. Immunol. 181, 3400-3412
   Abstract »    Full Text »    PDF »
Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice.
Y. Sun, D. P. Witte, H. Ran, M. Zamzow, S. Barnes, H. Cheng, X. Han, M. T. Williams, M. R. Skelton, C. V. Vorhees, et al. (2008)
Hum. Mol. Genet. 17, 2345-2356
   Abstract »    Full Text »    PDF »
Involvement of Secretory and Endosomal Compartments in Presentation of an Exogenous Self-Glycolipid to Type II NKT Cells.
K. C. Roy, I. Maricic, A. Khurana, T. R. F. Smith, R. C. Halder, and V. Kumar (2008)
J. Immunol. 180, 2942-2950
   Abstract »    Full Text »    PDF »
Role of NKT Cells in the Digestive System. III. Role of NKT cells in intestinal immunity.
S. Zeissig, A. Kaser, S. K. Dougan, E. E. S. Nieuwenhuis, and R. S. Blumberg (2007)
Am J Physiol Gastrointest Liver Physiol 293, G1101-G1105
   Abstract »    Full Text »    PDF »
Molecular imaging of membrane interfaces reveals mode of beta-glucosidase activation by saposin C.
J.-R. Alattia, J. E. Shaw, C. M. Yip, and G. G. Prive (2007)
PNAS 104, 17394-17399
   Abstract »    Full Text »    PDF »
Distinct Endosomal Trafficking Requirements for Presentation of Autoantigens and Exogenous Lipids by Human CD1d Molecules.
X. Chen, X. Wang, J. M. Keaton, F. Reddington, P. A. Illarionov, G. S. Besra, and J. E. Gumperz (2007)
J. Immunol. 178, 6181-6190
   Abstract »    Full Text »    PDF »
A distal effect of microsomal triglyceride transfer protein deficiency on the lysosomal recycling of CD1d.
Y. Sagiv, L. Bai, D. G. Wei, R. Agami, P. B. Savage, L. Teyton, and A. Bendelac (2007)
J. Exp. Med. 204, 921-928
   Abstract »    Full Text »    PDF »
The Niemann-Pick type C2 protein loads isoglobotrihexosylceramide onto CD1d molecules and contributes to the thymic selection of NKT cells.
N. Schrantz, Y. Sagiv, Y. Liu, P. B. Savage, A. Bendelac, and L. Teyton (2007)
J. Exp. Med. 204, 841-852
   Abstract »    Full Text »    PDF »
Combined saposin C and D deficiencies in mice lead to a neuronopathic phenotype, glucosylceramide and {alpha}-hydroxy ceramide accumulation, and altered prosaposin trafficking.
Y. Sun, D. P. Witte, M. Zamzow, H. Ran, B. Quinn, J. Matsuda, and G. A. Grabowski (2007)
Hum. Mol. Genet. 16, 957-971
   Abstract »    Full Text »    PDF »
Implications for invariant natural killer T cell ligands due to the restricted presence of isoglobotrihexosylceramide in mammals.
A. O. Speak, M. Salio, D. C. A. Neville, J. Fontaine, D. A. Priestman, N. Platt, T. Heare, T. D. Butters, R. A. Dwek, F. Trottein, et al. (2007)
PNAS 104, 5971-5976
   Abstract »    Full Text »    PDF »
Normal development and function of invariant natural killer T cells in mice with isoglobotrihexosylceramide (iGb3) deficiency.
S. Porubsky, A. O. Speak, B. Luckow, V. Cerundolo, F. M. Platt, and H.-J. Grone (2007)
PNAS 104, 5977-5982
   Abstract »    Full Text »    PDF »
Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules.
W. Yuan, X. Qi, P. Tsang, S.-J. Kang, P. A. Illarionov, G. S. Besra, J. Gumperz, and P. Cresswell (2007)
PNAS 104, 5551-5556
   Abstract »    Full Text »    PDF »
MTP regulated by an alternate promoter is essential for NKT cell development.
S. K. Dougan, P. Rava, M. M. Hussain, and R. S. Blumberg (2007)
J. Exp. Med. 204, 533-545
   Abstract »    Full Text »    PDF »
An N-Linked Glycan Modulates the Interaction between the CD1d Heavy Chain and beta2-Microglobulin.
C. Paduraru, L. Spiridon, W. Yuan, G. Bricard, X. Valencia, S. A. Porcelli, P. A. Illarionov, G. S. Besra, S. M. Petrescu, A.-J. Petrescu, et al. (2006)
J. Biol. Chem. 281, 40369-40378
   Abstract »    Full Text »    PDF »
IFN-beta-Mediated Up-Regulation of CD1d in Bacteria-Infected APCs.
G. Raghuraman, Y. Geng, and C.-R. Wang (2006)
J. Immunol. 177, 7841-7848
   Abstract »    Full Text »    PDF »
Saposin A Mobilizes Lipids from Low Cholesterol and High Bis(monoacylglycerol)phosphate-containing Membranes: PATIENT VARIANT SAPOSIN A LACKS LIPID EXTRACTION CAPACITY.
S. Locatelli-Hoops, N. Remmel, R. Klingenstein, B. Breiden, M. Rossocha, M. Schoeniger, C. Koenigs, W. Saenger, and K. Sandhoff (2006)
J. Biol. Chem. 281, 32451-32460
   Abstract »    Full Text »    PDF »
Impaired selection of invariant natural killer T cells in diverse mouse models of glycosphingolipid lysosomal storage diseases.
S. D. Gadola, J. D. Silk, A. Jeans, P. A. Illarionov, M. Salio, G. S. Besra, R. Dwek, T. D. Butters, F. M. Platt, and V. Cerundolo (2006)
J. Exp. Med. 203, 2293-2303
   Abstract »    Full Text »    PDF »
Chewing the fat on natural killer T cell development.
D. I. Godfrey, M. J. McConville, and D. G. Pellicci (2006)
J. Exp. Med. 203, 2229-2232
   Abstract »    Full Text »    PDF »
CD1d Ligands: The Good, the Bad, and the Ugly.
R. R. Brutkiewicz (2006)
J. Immunol. 177, 769-775
   Abstract »    Full Text »    PDF »
Cutting Edge: Impaired Glycosphingolipid Trafficking and NKT Cell Development in Mice Lacking Niemann-Pick Type C1 Protein.
Y. Sagiv, K. Hudspeth, J. Mattner, N. Schrantz, R. K. Stern, D. Zhou, P. B. Savage, L. Teyton, and A. Bendelac (2006)
J. Immunol. 177, 26-30
   Abstract »    Full Text »    PDF »
Gene expression patterns define novel roles for E47 in cell cycle progression, cytokine-mediated signaling, and T lineage development.
R. Schwartz, I. Engel, M. Fallahi-Sichani, H. T. Petrie, and C. Murre (2006)
PNAS 103, 9976-9981
   Abstract »    Full Text »    PDF »
Saposin B binds and transfers phospholipids.
F. Ciaffoni, M. Tatti, A. Boe, R. Salvioli, A. Fluharty, S. Sonnino, and A. M. Vaccaro (2006)
J. Lipid Res. 47, 1045-1053
   Abstract »    Full Text »    PDF »
DOCK2 Is Required in T Cell Precursors for Development of V{alpha}14 NK T Cells..
Y. Kunisaki, Y. Tanaka, T. Sanui, A. Inayoshi, M. Noda, T. Nakayama, M. Harada, M. Taniguchi, T. Sasazuki, and Y. Fukui (2006)
J. Immunol. 176, 4640-4645
   Abstract »    Full Text »    PDF »
Design of natural killer T cell activators: Structure and function of a microbial glycosphingolipid bound to mouse CD1d..
D. Wu, D. M. Zajonc, M. Fujio, B. A. Sullivan, Y. Kinjo, M. Kronenberg, I. A. Wilson, and C.-H. Wong (2006)
PNAS 103, 3972-3977
   Abstract »    Full Text »    PDF »
Lipid-binding Proteins in Membrane Digestion, Antigen Presentation, and Antimicrobial Defense.
T. Kolter, F. Winau, U. E. Schaible, M. Leippe, and K. Sandhoff (2005)
J. Biol. Chem. 280, 41125-41128
   Full Text »    PDF »
Structural basis for CD1d presentation of a sulfatide derived from myelin and its implications for autoimmunity.
D. M. Zajonc, I. Maricic, D. Wu, R. Halder, K. Roy, C.-H. Wong, V. Kumar, and I. A. Wilson (2005)
J. Exp. Med. 202, 1517-1526
   Abstract »    Full Text »    PDF »
The Influence of CD1d in Postselection NKT Cell Maturation and Homeostasis.
F. W. McNab, S. P. Berzins, D. G. Pellicci, K. Kyparissoudis, K. Field, M. J. Smyth, and D. I. Godfrey (2005)
J. Immunol. 175, 3762-3768
   Abstract »    Full Text »    PDF »
Microsomal triglyceride transfer protein lipidation and control of CD1d on antigen-presenting cells.
S. K. Dougan, A. Salas, P. Rava, A. Agyemang, A. Kaser, J. Morrison, A. Khurana, M. Kronenberg, C. Johnson, M. Exley, et al. (2005)
J. Exp. Med. 202, 529-539
   Abstract »    Full Text »    PDF »
Mycobacterium tuberculosis Regulates CD1 Antigen Presentation Pathways through TLR-2.
C. Roura-Mir, L. Wang, T.-Y. Cheng, I. Matsunaga, C. C. Dascher, S. L. Peng, M. J. Fenton, C. Kirschning, and D. B. Moody (2005)
J. Immunol. 175, 1758-1766
   Abstract »    Full Text »    PDF »
Expansion and Hyperactivity of CD1d-Restricted NKT Cells during the Progression of Systemic Lupus Erythematosus in (New Zealand Black x New Zealand White)F1 Mice.
C. Forestier, A. Molano, J. S. Im, Y. Dutronc, B. Diamond, A. Davidson, P. A. Illarionov, G. S. Besra, and S. A. Porcelli (2005)
J. Immunol. 175, 763-770
   Abstract »    Full Text »    PDF »
Point Mutational Analysis of the Liganding Site in Human Glycolipid Transfer Protein: FUNCTIONALITY OF THE COMPLEX.
M. L. Malakhova, L. Malinina, H. M. Pike, A. T. Kanack, D. J. Patel, and R. E. Brown (2005)
J. Biol. Chem. 280, 26312-26320
   Abstract »    Full Text »    PDF »
BCR targeting of biotin-{alpha}-galactosylceramide leads to enhanced presentation on CD1d and requires transport of BCR to CD1d-containing endocytic compartments.
G. A. Lang, P. A. Illarionov, A. Glatman-Freedman, G. S. Besra, and M. L. Lang (2005)
Int. Immunol. 17, 899-908
   Abstract »    Full Text »    PDF »
Modulation of CD1d-restricted NKT cell responses by using N-acyl variants of {alpha}-galactosylceramides.
K. O. A. Yu, J. S. Im, A. Molano, Y. Dutronc, P. A. Illarionov, C. Forestier, N. Fujiwara, I. Arias, S. Miyake, T. Yamamura, et al. (2005)
PNAS 102, 3383-3388
   Abstract »    Full Text »    PDF »
Lysosomal Glycosphingolipid Recognition by NKT Cells.
D. Zhou, J. Mattner, C. Cantu III, N. Schrantz, N. Yin, Y. Gao, Y. Sagiv, K. Hudspeth, Y.-P. Wu, T. Yamashita, et al. (2004)
Science 306, 1786-1789
   Abstract »    Full Text »    PDF »
Mutation in saposin D domain of sphingolipid activator protein gene causes urinary system defects and cerebellar Purkinje cell degeneration with accumulation of hydroxy fatty acid-containing ceramide in mouse.
J. Matsuda, M. Kido, K. Tadano-Aritomi, I. Ishizuka, K. Tominaga, K. Toida, E. Takeda, K. Suzuki, and Y. Kuroda (2004)
Hum. Mol. Genet. 13, 2709-2723
   Abstract »    Full Text »    PDF »
New issues in tuberculosis.
S H E Kaufmann (2004)
Ann Rheum Dis 63, ii50-ii56
   Abstract »    Full Text »    PDF »
IMMUNOLOGY: The Robin Hood of Antigen Presentation.
G. De Libero (2004)
Science 303, 485-487
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882